3  Microenvironment originating inflammatory cues
The extracellular matrices (ECMs), are complex, multi-constituent meshes that surround and support cells in tissues, with a regulatory role in all biological processes, as well as in tissue organization (Hynes, 2009). The ECMs are composed of fibrillar proteins and proteoglycans, as well as glycosaminoglycans specifically organized as modules or domains. The ECM suprastructure can be envisaged as a “platform” receiving, and simultaneously, delivering a myriad of signals to cells that are crucial to homeostasis, but also contributing to the progression of various pathologies (Sifaki et al., 2006; Tzanakakis et al., 2018, 2019). Importantly, the inflammation-mediated alterations in the ECM result in release of active mediators crucial to disease progression (Kavasi et al., 2017; Neagu et al., 2019; Nikitovic et al., 2015). Noteworthy, the effects exerted by remodelled ECM are cell and tissue type dependent exerting thus, specific influence to discrete tissue compartments (Nikitovic et al., 2014a).
Recent developments highlighted the importance of ECM remodelling in metabolic disease and obesity as well as the associated inflammation (Ruiz-Ojeda et al., 2019). Indeed, it was suggested that both the specific remodelling of adipose tissue ECM organization and dysregulated intracellular signalling processes may be correlated with obesity-associated insulin resistance (Guzman-Ruiz et al., 2020). The main components of adipose tissue ECM are collagens, fibronectin and laminin (Mori et al., 2014). Minor constituents include osteopontin, hyaluronan (HA), thrombospondins, MMPs, as well as A disintegrin and metalloproteinase domain-containing protein (ADAMs), and contribute significantly to ECM remodelling and the regulation of adipose tissue functions (Lin et al., 2016).
The main characteristic of obesity is an increase in lipid tissue infiltration due to the hypertrophy of existing adipocytes, as well as due to the hyperplasia of adipocytes resulting from de novo adipogenesis from precursor stem cells (Schoettl et al., 2018). Indeed, it was postulated that the ECM, in a spatial as well as temporal manner, regulates adipogenesis (Soukas et al., 2001). In addition to adipocyte deposition, a notable migration of macrophages and vascular cells was correlated to changes in the ECM structure. This remodelling leads to the release of active mediators that can affect immune cells’ recruitment and activation, facilitating the inflammatory state of lipid tissue. Furthermore, the strong upregulation of obese adipose tissue ECM components, including collagens and osteopontin, was suggested to initiate the necrosis of adipocytes, enhance the infiltration of immune cells, leading to tissue inflammation and metabolic dysfunction (Catalan et al., 2012; Ruiz-Ojeda et al., 2019). Thus, the overexpression of endotrophin, resulted from the cleavage of the α-3 chain of collagen VI (Col6a3), facilitates the deposition of fibrotic collagen and initiates adipose tissue inflammation and insulin resistance (Sun et al., 2014). A recent study demonstrated that the expression of MMP14 is strongly upregulated in the adipose tissue of transgenic obese mice. Interestingly, MMP14 proteolytic activity results in the release of endotrophin with concurrent formation of enlarged adipocytes and increase in body weight, altered lipid metabolism and insulin resistance (Li et al., 2020). Furthermore, Springer et al. recently demonstrated a link between alterations in the ECM of obese women and breast cancer. Thus, enhanced adipose tissue interstitial fibrosis facilitates the generation of M2/M1 type macrophages pattern similar to that of tumour-associated macrophages, as well as the generation of associated inflammatory cues (Springer et al., 2019). Under these conditions a paracrine loop consisting of free fatty acids and TNF-α is established among adipocytes and infiltrating macrophages that enhances inflammation-mediated alterations in the adipose tissue (Engin, 2017). Recently, lumican, a small leucine-rich proteoglycan (Nikitovic et al., 2014b), was shown to be overexpressed in ECM of subcutaneous fat of insulin resistant obese individuals. Lumican was demonstrated to alter the organization of collagen I, dysregulate adipogenesis and trigger oxidative stress, facilitating the pathology of obesity-associated insulin resistance (Guzman-Ruiz et al., 2020). A separate study showed that the effect of lumican was diet-dependent and correlated to adipose tissue inflammation. Indeed, the same authors suggest that the ECM protein lumican could pose a convergent point among the ECM, the glucose homeostasis and the metabolic syndrome (Wolff et al., 2019).
Osteopontin, an ECM glycoprotein, excessively secreted by adipose tissue macrophages (Nomiyama et al., 2007) enhances adipose tissue inflammation and facilitates the onset of insulin resistance (Aouadi et al., 2013). Another important ECM component, the glycosaminoglycan HA, has been strongly correlated to increased inflammatory burden, including cancer-associated (Nikitovic et al., 2015) and sterile inflammation (Kavasi et al., 2017, 2019; Nikitovic et al., 2014b). The biologic role of HA is dependent on its size. Thus, high molecular weight HA (HMWHA), physiologically secreted by cells facilitates normal tissue stability (Kavasi et al., 2017). In contrast, low molecular weight HA (LMWHA) fragments, produced via enzymatic action or chemical reactions, are pro-inflammatory and have been characterized as a danger-associated molecular patterns (DAMP) (Kavasi et al., 2017, 2019; Nikitovic et al., 2014a). Indeed, the generated LMWHA fragments can trigger a Toll-like receptor 4 (TLR4)/NF-κB signalling pathway to regulate inflammatory genes transcription in immune cells (Kavasi et al., 2017; Termeer et al., 2002). Interestingly, HA levels were increased in various tissues of type-2 diabetes mellius (T2DM), but not in type-1 (T1DM) subjects, and independent of glycaemic control. Taking into account that T2DM, in contrast to T1DM, is linked with systemic inflammation, it was suggested that inflammatory factors and not hyperglycaemia upregulate HA levels (Nagy et al., 2019). Importantly, it was demonstrated that the expression of genes involved in the metabolism of HA was positively correlated to the process of adipocyte differentiation (Allingham et al., 2006). Recently, it was shown that HA exerts inhibitory effects in vitro regarding adipogenesis of 3T3-L1 cells, whereas downregulating HA prevented insulin resistance and NAFLD correlated to excess deposition of abdominal fat in HFD-feeding C57BL/6J mouse model (Ji et al., 2014). Moreover, treatment of HFD-fed obese mice with a stable hyaluronidase complex, where human recombinant hyaluronidase was Pegylated, was shown to decreases adiposity, adipose tissue inflammation and insulin resistance (Kang et al., 2013).
A hallmark of metabolic diseases is a high NADH/NAD+ ratio, originating from excessive electron supply. This dysregulation results in an altered mitochondrial function and sirtuin-3 (SIRT-3) activity, which result in oxidative stress and distorted fatty acid β-oxidation (Cortes-Rojo et al., 2020). Increased ROS production was shown to induce excessive remodelling of the ECM in a pathological milieu (Nikitovic et al., 2013). Thus, oxidative stress induced by high-glucose levels, in rat glomerular mesangial cells, resulted in an increased deposition of collagen IV and fibronectin, through the involvement of the TXNIP-NLRP3 inflammasome signalling (Wang et al., 2017). Importantly, the remodelling of renal ECM is involved in the progression of diabetic nephropathy, one of the most serious complications of diabetes mellitus. Treatment aimed at downregulating ROS generation, such as the utilization of dihydroquercetin (DHQ), an important natural dihydroflavone, attenuated the activation of NLRP3 inflammasome and the subsequent of increased deposition to ECM of renal fibrosis-associated proteins upon exposure of renal cells to high glucose levels (Ding et al., 2018).
These data highlight the complex interactions between the ECM, inflammation, and metabolic diseases. The reorganization of the ECM as well as ECM-originating pro-inflammatory cues needs to be taken account when designing efficient therapy for inflammation associated disease. Dietary measures might constitute important means to mitigating these pathological pathways.